The Clinical Epilepsy Section has been developing and testing new techniques to improve seizure control, medication tolerance, and rehabilitation in patients with severe epilepsy. Patients with uncontrolled seizures are admitted for a complete evaluation, including simultaneous video and telemetered EEG recording of seizures, daily determinations of antiepileptic drug serum concentrations, positron emission tomography (PET), magnetic resonance imaging (MRI), and magnetoencephalography (MEG). A specific seizure diagnosis is established allowing each patient to be assigned to an appropriate research protocol and therapy. PET in patients with localized brain lesions has demonstrated focal hypometabolic cerebral areas corresponding to the interictal seizure EEG focus. In some patients, PET has been able to detect a focus when other methods have failed. Studies of patients during partial seizures have shown a change from hypo to hypermetabolism at the site of the focus. In the Lennox-Gastaut syndrome, PET has revealed the existence of two separate metabolic patterns despite clinical seizure similarity. PET studies allow more definitive overall identification of the epileptic lesion and suggest new avenues of investigation into the basic mechanisms of the epilepsies. MRI may show small structural lesions underlying PET hypometabolism even when CT is normal. Further studies will elucidate the relation of metabolic and pathologic changes. MEG may have the potential to accurately localize the subsurface origin of spikes. EEG provides little information on the spatial distribution of epileptiform in cortical depths; MEEG may be superior.